With targeted immuno-oncology therapies showing promise in clinical trials, competition has increased among biotech firms to bring products to the market. One approach to immuno-oncology treatment that is becoming more popular involves checkpoint inhibitors. In fact, the surge in research on certain regulatory checkpoints has helped to reinvigorate the field of immuno-oncology in recent years.
The Biology Behind Checkpoint Inhibitors
In order to understand how checkpoint inhibitors work, it is important to look at the typical immune response to cancer. The body’s immune system has evolved to distinguish between its own tissues and foreign invaders. However, the system also has its own checks and balances that down-regulate its responses to avoid harm to healthy cells.
A number of solid tumor cancer cells produce antigens that the immune system recognizes and responds to in order to stop growth or control development. The process is referred to as immunosurveillance. The immune-editing theory holds that the immune response to tumors is a balancing act that involves both the innate and acquired immune system. While the immune system tries to inhibit tumor growth, it is not always successful, and the tumors sometimes grow to become clinically apparent.
The immune system may struggle to eradicate or suppress cancerous masses for a range of reasons. Outside of inhibitory processes like cytokines, suppressor cells, and metabolism, researchers have identified a few key reasons that serve as the basis for modern immuno-oncology therapies. First, the immune system may struggle to distinguish between normal and cancerous cells. Second, the immune system may not have the resources necessary to launch a strong enough attack. Third, cancer cells may produce proteins that suppress the immune response and render helper T-cells and antigen-specific cytotoxic cells ineffective. The latter situation is what has led to the development of checkpoint inhibitors.
How the Immune System Mounts an Attack
When the immune system encounters a foreign cell, its killer cells will destroy it, causing it to disintegrate into peptide fragments. In turn, these fragments are processed by antigen presenting cells, which are activated to release cytokines that cause an inflammatory response. In addition, antigen presenting cells produce specialized molecules on the surface of the cells that present antigenic peptides to T-cell receptors using the human leukocyte antigen system. T-cells are activated when proteins bind at two different sites, TCR-MCH and B7-CD28.
When CD8+ T-cells bind to cells that express the surface molecules, known as major histocompatibility complexes, they are transformed into cytotoxic T-cells, which can cause cell death through apoptosis. CD4+ T-cells bind to surface proteins to trigger cytokine release and transformation into a tumor-specific antibody-secreting plasma cell.
The body has natural inhibitory checkpoints to down-regulate T-cell activity and to prevent these cells from attacking healthy tissues. In particular, CTLA-4 is found on both naive and memory T cells. During T-cell activation, CTLA-4 is up-regulated to put the brakes on the immune system. By blocking the CTLA-4 receptor, T-cell production resumes and the body continues to fight the tumor. However, removing this feedback loop can result in damage to normal tissues.
Another important factor in immune regulation is PD-1 and its ligand PD-L1 and PD-L2, which is present in peripheral tissues. PD-1 prevents the overstimulation of the immune response and promotes self-antigen tolerance. PD-1 is expressed later in the immune response than CTLA-4, and many immune cells produce it, including activated T-cells.
Inhibiting the Natural Biological Checkpoints
Activated T-cells naturally produce interferons that trigger the expression of PD-L1. However, PD-L1 is also expressed by hematologic malignancies, including several types of cancer, ranging from melanoma to lymphoma. Many researchers believe that this co-opting of the PD-1 and PD-L1 pathway is one of the primary methods that cancers have evolved to avoid the typical immune response. As soon as cytotoxic T-cells are triggered to kill the tumor cell, that cell expresses PD-L1, which engages with the T-cell PD-1 and causes apoptosis of the T-cell. This cancer-induced immunosuppression can be reversed by disrupting the pathway, which is the goal of checkpoint inhibitors.
Initial data from preclinical research and early studies have looked at the effects of stopping both the CTLA-4 pathway, thereby preventing the natural brakes placed on the immune system, and the PD-1 pathway to prevent tumors from halting the immune attack. Research has confirmed that targeting these pathways simultaneously resulted in better response rates than when either is targeted alone. However, targeting both pathways increases the chance of treatment-related adverse immune events, which has occurred in a large number of patients.
Most of the adverse events experienced are low-grade and therefore tolerable. As one might suspect based on the biology of these checkpoint pathways, the anti-PD-1 and anti-PDL1 agents have fewer side effects than agents used to block the CTLA-4 pathway. At the same time, pneumonitis seems to be more commonly associated with PD-1 inhibitors than CTLA-4 inhibitors. Side effects most commonly involve dermatologic and gastrointestinal issues, although the hepatic and endocrine systems may also be affected. Fatigue is also a common side effect.